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A study was conducted to evaluate the effect of characteristics patients' gender, age, weight, height, and body surface area, as well as the concurrent or recent use of opioids, ethanol and tobacco, on opioid dose requirements during administration of patient-controlled analgesia (PCA). Data were collected retrospectively from the medical records of 150 patients who underwent open cholecystectomies during an 18 month period at one institution. Demonstrable inter-patient variability in patterns of PCA use was observed. The results of the study demonstrate that during the first 48 hours of PCA therapy, patient age, height, weight, body surface area, gender, smoking, alcohol use, and preoperative opioid use may have significant influence on opioid analgesic use (p < 0.05). The data support the hypothesis that patient-specific factors may contribute to the variability observed in patients' PCA analgesic dose requirements, and these factors should be considered when selecting a proper demand (bolus) dose for PCA therapy. [ABSTRACT FROM AUTHOR]

The effects of sex, ethnicity, and genetic polymorphism on hepatic CYP2B6 (cytochrome P450 2B6) expression and activity were previously demonstrated in vitro. Race/ethnic differences in CYP2B6 genotype and phenotype were observed only in women. To identify important covariates associated with interindividual variation in CYP2B6 activity in vivo, we evaluated these effects in healthy volunteers using bupropion (Wellbutrin SR GlaxoSmithKline, Research Triangle Park, NC) as a CYP2B6 probe substrate. A fixed 150-mg oral sustained-release dose of bupropion was administered to 100 healthy volunteers comprising four sex/ethnicity cohorts (n = 25 each): Caucasian men and Caucasian, African American, and Hispanic women. Blood samples were obtained at 0 and 6 hours postdose for the measurement of serum bupropion (BU) and hydroxybupropion (HB) concentrations. Whole blood was obtained at baseline for CYP2B6 genotyping. To characterize the relationship between CYP2B6 activity and ethnicity, sex, and genotype when accounting for serum BU concentrations (dose-adjusted log(10)-transformed), analysis of covariance model was fitted in which the dependent variable was CYP2B6 activity represented as the log(10)-transformed, metabolic ratio of HB to BU concentrations. Several CYP2B6 polymorphisms were associated with CYP2B6 activity. Evidence of dependence of CYP2B6 activity on ethnicity or genotype-by-ethnicity interactions was not detected in women. These results suggest that CYP2B6 genotype is the most important patient variable for predicting the level of CYP2B6 activity in women, when measured by the metabolism of bupropion. The bupropion metabolic ratio appears to detect known differences in CYP2B6 activity associated with genetic polymorphism, across different ethnic groups. Prospective studies will be needed to validate the use of bupropion as a probe substrate for clinical use.

Purpose: Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors., Methods: Patients received bortezomib, 0.9-1.5 mg/m(2), on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m(2), on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination., Results: A total of 37 patients with four median prior therapies were treated. Frequent grade 1-2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1 of 6 patients receiving bortezomib at 1.2 mg/m(2), and grade 3 nausea, vomiting, and diarrhea in 1 of 6 patients receiving bortezomib at 1.5 mg/m(2). Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m(2) levels, bortezomib at 1.3 mg/m(2) and PLD at 30 mg/m(2) are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs., Conclusions: A regimen of bortezomib, 1.3 mg/m(2) on days 1, 4, 8, and 11 with PLD, 30 mg/m(2), on day 4 of a 21-day cycle, was safe in this study, and merits further investigation.

Background: Nelarabine was approved by the US Food and Drug Administration (FDA) in October 2005 for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that has not responded to or has relapsed after treatment with at least 2 chemotherapy regimens., Objectives: This article reviews the pharmacology, mechanism of action, and pharmacokinetic and pharmacodynamic properties of nelarabine. Also reviewed are nelarabine's clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies; its toxicity profile, dosage, and administration; and areas of ongoing and future research., Methods: Relevant literature was identified through searches of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and the American Society of Hematology database (2003-2006) using the terms nelarabine, Arranon, 506U78, and 2-amino-6-methoxypurine arabinoside. The reference lists of the identified articles were searched for additional sources. Product information obtained from the manufacturer of nelarabine was consulted, as were the FDA reviews of nelarabine. All identified publications were considered, and those meeting the objectives of this review were included., Results: Nelarabine, a soluble prodrug of 9-beta-D- arabinofuranosylguanine (ara-G), is a novel purine antimetabolite antineoplastic that preferentially accumulates in T-cells. Ara-G is rapidly phosphorylated in T-cells to ara-G triphosphate (ara-GTP), which exerts cytotoxic effects. Renal elimination of ara-G is decreased in patients with mild to moderate renal impairment; however, no dose adjustment is recommended. Accumulation of ara-GTP occurs in T-cells in a dose-dependent manner, leading to preferential cytotoxicity. Nelarabine has activity in T-cell malignancies, as evaluated in 2 Phase I and 5 Phase II studies. It received accelerated approval from the FDA based on the resuits of 2 Phase II trials, one in pediatric patients (PGAA 2001) and the other in adults (CALGB 19801). In PGAA 2001, patients with T-ALL in first relapse (n = 33) had an objective response rate of 55% (16 with a complete response [CR] and 2 with a partial response [PR]), and those with T-ALL in second relapse (n = 30) had an objective response rate of 27% (7 CR and 1 PR). Among patients with central nervous system-positive T-ALL or T-cell non-Hodgkins lymphoma (T-NHL) (n = 21), 33% had an objective response (5 CR and 2 PR); among patients with T-ALL or T-NHL with extramedullary relapse (n = 22), 14% had a PR. CALGB 19801 included 39 adult patients with T-cell malignancies, of whom 7 (18%) had a CR and an additional 2 (5%) had a CR without full hematologic recovery. The recommended dose of nelarabine in adults is 1500 mg/m(2) IV given over 2 hours on days 1, 3, and 5, repeated every 21 days; the recommended dose in pediatric patients is 650 mg/m(2) IV given over 1 hour for 5 consecutive days, repeated every 21 days. Dose-limiting toxicities observed in the Phase I and II trials included central and peripheral neurotoxicity. Symptoms of central neurotoxicity included somnolence, seizures, dizziness, confusion, and ataxia; symptoms of peripheral neurotoxicity included paresthesias, pain in the extremities, and peripheral neuropathy., Conclusions: Nelarabine is indicated for the treatment of T-ALL and T-LBL that has not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. Objective response rates in Phase II clinical trials of nelarabine have ranged from 11% to 60%. Use of nelarabine is limited by potentially severe neurotoxicity.

Limited data are available about the effect of steady-state lopinavir and ritonavir (LPV/r) on bupropion pharmacokinetics. As patients may benefit by using these two agents in combination, this study determined the extent and direction of this drug-drug interaction. Twelve healthy volunteers received a single 100 mg dose of sustained-release bupropion before and after 2 weeks of treatment with LPV/r 400 mg/100 mg twice daily. Pharmacokinetics profiles were determined on days 1 and 30 for bupropion and hydroxybupropion and days 29 and 30 for LPV/r. LPV/r administration significantly decreased bupropion maximum plasma concentration (C(max)) by 57% (90% confidence interval (CI), 38-76%; P<0.01) and area under the curve (AUC) infinity by 57% (90% CI, 32-83%; P<0.01). Hydroxybupropion C(max) and AUC infinity decreased by 31% (90% CI, 7-55%; P<0.01) and by 50% (90% CI, 34-65%; P<0.01), respectively. No significant changes in the pharmacokinetics of LPV/r were found following administration of a single dose of bupropion. Concurrent use of LPV/r and bupropion resulted in decreased exposure to bupropion and its active metabolite hydroxybupropion that may necessitate as much as a 100% dose increase of bupropion. A probable mechanism for this interaction is the concurrent induction of cytochrome P450 2B6 and UDP-glucuronosyltransferase enzymes. LPV/r exposure is unaffected by a single dose of bupropion.

Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.

A tularemia outbreak, caused by Francisella tularensis type B, occurred among wild-caught, commercially traded prairie dogs. F. tularensis microagglutination titers in one exposed person indicated recent infection. These findings represent the first evidence for prairie-dog-to-human tularemia transmission and demonstrate potential human health risks of the exotic pet trade.

The purpose of this investigation was to evaluate the role of cytochrome P450 (CYP) 3A4 in human liver microsomal bupropion (BUP) hydroxylation. Across the BUP concentration range of 0.075 to 12 mM, cDNA-expressed CYP3A4 demonstrated BUP hydroxylase activity only when incubated with concentrations > or =4 mM. When assayed at 12 mM BUP, cDNA-expressed CYP3A4 catalyzed BUP hydroxylation at a 30-fold lower rate than cDNA-expressed CYP2B6 (0.2 versus 7 pmol/min/pmol of P450). Among a panel of 16 human liver microsomes (HLMs), BUP hydroxylase activity varied 80-fold when assayed at 500 microM and did not strongly correlate with testosterone 6beta-hydroxylase activity when assayed at 250 microM testosterone (r(2) = 0.39), nor with CYP3A4 protein expression. A selective CYP3A4 inhibitor, troleandomycin (TAO), did not significantly alter rates of BUP hydroxylation when assayed in a moderate activity HLM at 10 to 2000 microM BUP, as reflected by a similarity in the kinetic parameters of BUP hydroxylation in the absence or presence of TAO. In addition, the same range of TAO concentrations (0.025-100 microM) that inhibited testosterone 6beta-hydroxylation in a concentration-dependent manner (46-81%) in pooled HLMs produced negligible inhibition (7%) of BUP hydroxylation when assayed at 500 microM BUP. These results suggest that CYP3A4 does not significantly catalyze BUP hydroxylation. Furthermore, these results complement recent data supporting selectivity of BUP hydroxylation for CYP2B6 at 500 microM BUP.

Objective: To describe a systematic evaluation of the outcomes associated with revising institutional guidelines for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) to promote cost-effective use of the serotonin (5-HT3) antagonists., Methods: The 5-HT3 antagonist of choice in the antiemetic guidelines was revised from intravenous ondansetron to oral granisetron in August 1995. Patient assessments were conducted immediately prior to (Period 1) and after (Period 2) guideline revision using validated questionnaires. The effectiveness of the two 5-HT3 antagonists were compared and reported to the prescribing oncologists. Outcomes were assessed one year after guideline revision (Period 3) using identical methods., Results: No difference was found in the rate of total control (no emesis, no nausea) between patients receiving oral granisetron (60%) and intravenous ondansetron (56%) (p = 0.408, Period 1 vs. 2). Nausea severity, the number of emesis episodes, and use of rescue antiemetics were also equivalent. Prescriber compliance with using the 5-HT3 antagonist of choice and dose increased from 48% to 61% following adoption of oral granisetron. By Period 3, compliance increased to 78%, and satisfactory control of acute CINV was again documented. The costs for prevention of acute CINV decreased from $107 in Period 1 (intravenous ondansetron only) to $65 in Period 3 (oral granisetron)., Conclusions: Outcomes associated with use of oral granisetron and intravenous ondansetron were equivalent in this patient population. Guideline revision and outcome documentation by the oncology pharmacists resulted in increased compliance with institution guidelines and a 40% cost savings.

The purpose of this study was to establish bupropion (BUP) hydroxylation as a selective in vitro marker of cytochrome P450 (CYP) 2B6 catalytic activity. Among a panel of 16 human liver microsomes (HLMs), BUP hydroxylase activity varied 80-fold when assayed at 500 microM substrate and significantly correlated with CYP2B6 blotting density (r(2) = 0.99) and S-mephenytoin N-demethylase activity (r(2) = 0.98). Kinetic analysis of BUP hydroxylation was performed in a subset of seven HLMs representative of the 80-fold range in activity. Sigmoidal kinetics suggestive of allosteric activation was observed in five HLMs exhibiting low or high activity; the mean apparent K(m) for BUP hydroxylation in these HLMs (130 microM) was similar to the K(m) for cDNA-expressed CYP2B6 (156 microM). Nonsaturable, biphasic kinetics was observed in two HLMs exhibiting low activity. Among a panel of cDNA-expressed P450 isoforms, CYP2B6 and CYP2E1 demonstrated the highest rates of BUP hydroxylation at 12 mM BUP (7.0 and 2.4 pmol/min/pmol of P450, respectively). The relative contributions of CYP2B6 and CYP2E1 to BUP hydroxylation were estimated by using immunoinhibitory monoclonal antibodies (MAB) to these enzymes. MAB-2B6 produced 88% maximum inhibition of BUP hydroxylation when assayed at 12 mM BUP in a high activity HLM, whereas MAB-2E1 produced 81% maximum inhibition in a low activity HLM. However, negligible inhibition by MAB-2E1 was observed when low and high activity HLMs were assayed at 500 microM BUP. These results demonstrate selectivity of BUP hydroxylation for CYP2B6 at 500 microM BUP, thereby validating its use as a diagnostic in vitro marker of CYP2B6 catalytic activity.

The indications, pharmacokinetics, and therapeutic guidelines for available coagulation products are reviewed. Patients with hemophilia, von Willebrand's disease (VWD), or acquired inhibitors to antihemophilic factor (AHF) cannot spontaneously stop an acute hemorrhage. Coagulation products used to manage bleeding in patients with these disorders include AHF concentrates, factor IX concentrates, factor VIIa concentrate, factor IX complexes, anti-inhibitor coagulant complexes, and desmopressin acetate. Typically, these commercially available products are used to manage acute bleeding or to prevent excessive bleeding during surgery. The dosage of the coagulation products and the duration of therapy depend on many variables, including the severity of the hemorrhage, the pharmacokinetics of the coagulation products, and patient-specific factors. Product purity and viral attenuation are also important considerations in determining an appropriate dosage regimen. Recombinant versions of some coagulant factors are available and can eliminate the risk of viral transmission. A thorough understanding of each coagulation product can guide product selection, dosing, and treatment duration and can reduce the risk of viral transmission.

Objective: To conduct a retrospective drug utilization evaluation comparing the use of granulocyte colony-stimulating factor (G-CSF) at a university medical center with the American Society of Clinical Oncology (ASCO) CSFs Practice Guidelines., Methods: Patients who received G-CSF from June 1, 1996, to December 31, 1996, were identified through the pharmacy computer system and the medical records were reviewed for a randomly selected sample of 26% of the 289 patients identified. Outpatient, inpatient, and electronic medical records were reviewed for the indication, dosage, day of initiation, day of discontinuation, and absolute neutrophil count (ANC) monitoring plan for each course of G-CSF; these records were subsequently compared with the ASCO guidelines., Results: The use of G-CSF after chemotherapy was evaluated in 51 patients who received a total of 182 courses of G-CSF. The goal of chemotherapy was curative in 61% of courses. Sixty-five percent of G-CSF courses were prescribed for primary prophylaxis. Of these, 74% followed chemotherapy in patients with an expected incidence of febrile neutropenia > or =40% or followed chemotherapy in patients with compromised marrow reserve secondary to extensive prior therapy or in patients older than 60 years. Most of the G-CSF courses (75%) were rounded to the nearest vial size. The areas of greatest departure from the ASCO guidelines included aspects of initiation and discontinuation of G-CSF courses and inadequate documentation of ANC recovery., Conclusions: These results demonstrate a number of specific opportunities for oncology pharmacists to improve the use of G-CSF in patients receiving chemotherapy. Recommendations were made to the pharmacy and therapeutics committee and medical oncologists to improve compliance with the ASCO guidelines.

It is widely believed that patients' reluctance to report pain and adhere to treatment recommendations are significant barriers to cancer pain control. However, few investigators have examined barriers to cancer pain management from the cancer patient's perspective. Ambulatory patients with cancer who had experienced cancer-related pain in the previous month or were currently taking analgesics for cancer pain control were asked to participate in this study. Information regarding (a) pain assessment, (b) pain medication use, (c) concerns and barriers to compliance, (d) communication patterns regarding pain and pain control, and (e) demographics were collected during a 10-min structured interview. Approximately 20% of patients with a current cancer diagnosis who were approached reported that they had experienced pain or taken analgesic drugs during the preceding month. Eighty-eight percent of these patients ranked their pain as five or greater (scale, 0-10), and 81% reported impaired function due to pain. Major barriers to effective treatment included forgetfulness, the belief that pain should be tolerated, concerns about side effects, and fear and disdain of dependence, addiction, and tolerance. One-third of patients felt that their pain could not be better controlled than it currently was. Patients reported frequent communication regarding pain and pain control with physicians (52%), nurses (41%), and pharmacists (17%). The low pain prevalence, coupled with high pain intensity and associated dysfunction, appears to be a reflection of patient's unwillingness to report pain of mild to moderate intensity. In addition to previously recognized factors, stoicism and fatalism represent significant barriers to cancer pain control.

Current therapy for hemophilia B requires large intravenous doses of factor IX (F.IX) given in the clinic or at home. Although home therapy is possible for many patients, it is often complicated by factors such as the lack of good venous access. Very little is known about extravascular routes for administering proteins like F.IX (57 kD) or other vitamin K-dependent procoagulant factors into the circulation. Questions about the absorption rate from extravascular administration as well as plasma recovery and bioavailability have arisen recently with the growing availability of highly purified procoagulant proteins and increased interest in gene therapy of hemophilia B. Therefore, a group of studies were undertaken to determine the absorption rate, plasma recovery, and bioavailability of high purity, human plasma-derived F.IX concentrates administered via extravascular routes in hemophilia B dogs and in one human hemophilia B subject. Five hemophilia B dogs were given human F.IX via either a subcutaneous (s.c.), intramuscular (i.m.), intraperitoneal (i.p.) or intravenous (i.v.) route. In a subsequent study, a single SC administration of human F.IX was compared to an identical i.v. dose of F.IX in the human hemophilia B subject. All extravascular routes of F.IX administration in both the canine and human gave lower levels of circulating plasma F.IX than the i.v. route, however all routes resulted in measurable F.IX activity. Of the extravascular routes, the i.m. injection in the canine resulted in a bioavailability of 82.8%, while the s.c. injection resulted in a bioavailability of 63.5%. F.IX reached the plasma compartment by all extravascular routes used, confirming that F.IX can be absorbed extravascularly. The duration of measurable F.IX activity following extravascular administration is prolonged beyond that typically seen with i.v. administration. These data show that significant levels of F.IX may be obtained via s.c. injection in canine and human hemophilia B subjects and further highlight the potential of extravascular routes of administration for future experimental and clinical uses of F.IX and other procoagulant proteins.

Purpose: To propose a classification of the acute emetogenicity of antineoplastic chemotherapy agents, and to develop an algorithm to define the emetogenicity of combination chemotherapy regimens., Methods: A Medline search was conducted to identify (1) clinical trials that used chemotherapy as single-agent therapy, and (2) major reviews of antiemetic therapy. The search was limited to patients who received commonly used doses of chemotherapy agents, primarily by short (< 3 hours) intravenous infusions. Based on review of this information and our collective clinical experience, we assigned chemotherapy agents to one of five emetogenic levels by consensus. A preliminary algorithm to determine the emetogenicity of combination chemotherapy regimens was then designed by consensus. A final algorithm was developed after we analyzed a data base composed of patients treated on the placebo arms of four randomized antiemetic trials., Results: Chemotherapy agents were divided into five levels: level 1 (< 10% of patients experience acute [< or = 24 hours after chemotherapy] emesis without antiemetic prophylaxis); level 2 (10% to 30%); level 3 (30% to 60%); level 4 (60% to 90%); and level 5 (> 90%). For combinations, the emetogenic level was determined by identifying the most emetogenic agent in the combination and then assessing the relative contribution of the other agents. The following rules apply: (1) level 1 agents do not contribute to the emetogenic level of a combination; (2) adding > or = one level 2 agent increases the emetogenicity of the combination by one level greater than the most emetogenic agent in the combination; and (3) adding level 3 or 4 agents increases the emetogenicity of the combination by one level per agent., Conclusion: The proposed classification schema provides a practical means to determine the emetogenic potential of individual chemotherapy agents and combination regimens during the 24 hours after administration. This system can serve as a framework for the development of antiemetic guidelines.

The demographics of home care pharmacists and the frequency and perceived importance of home care pharmacy tasks were studied. Two questionnaires were mailed in August 1994 to each of 1420 sites that provide home care pharmacy services. Home care pharmacists were asked to provide information on themselves and their companies and to rate 47 home care pharmacy tasks (administrative, clinical, distributive, and miscellaneous) on how often they are performed as part of the job and how essential they are for successful job performance. Of the 2840 surveys mailed to the 1420 sites, questionnaires for 87 sites were not deliverable, leaving an adjusted gross sample of 1333 sites. A total of 393 usable questionnaires were received from 326 sites (net site response rate 24.5%). Respondents tended to be male, have a B.S. degree only, and have more than six years' home care experience. The most commonly identified type of employer was an independent company. Some 34% of respondents said their company had only 1 site; another 33% stated more than 50 sites. Forty-three percent of locations had 2 pharmacist full-time equivalents. Distributive tasks had the highest frequency scores; clinical tasks were performed second most frequently. Distributive and clinical tasks also received high importance scores. The data suggests that, despite other demands on their time, home care pharmacists give considerable attention to tasks consistent with pharmaceutical care. A survey of home care pharmacists provided baseline information on demographics and the frequency and perceived importance of specific tasks.

Placement of a urethral catheter has been recommended to ensure adequate methotrexate elimination in patients with a neobladder; however, the need for this and its impact on methotrexate elimination have not been determined. A 53-year-old man with a cecal continent urinary diversion received intravenous methotrexate 30 mg/m2 on two occasions, with and without urethral catheter drainage of the neobladder. Serum methotrexate concentrations declined at a rate that resulted in 24- and 48-hour values falling below the accepted toxic concentration threshold of 5-50 mumol/L, and 0.05 mumol/L, respectively. In this man, who received low-dose methotrexate, catheterization of the neobladder did not alter methotrexate elimination sufficiently to justify its cost, risk, and inconvenience.

Objective: To assess pharmacists' knowledge, attitudes, and beliefs regarding the use of narcotics in cancer pain management, identify pharmacist counseling activities for cancer pain patients, assess pharmacy-related barriers to cancer pain management, and evaluate the availability of narcotic analgesics., Methods: Mailing of a six-page survey., Setting: Five hundred randomly selected pharmacists registered in North Carolina., Participants: Of 500 pharmacists surveyed, 141 surveys were completed and returned for a response rate of 28.2 percent., Results: Pharmacists surveyed were knowledgeable regarding the problem of undertreatment of cancer pain. More than 80 percent of respondents replied that most cancer patients experience pain at some time during their illness. Eighty-five percent of respondents agreed that the nurse must believe the patient's report of pain and that the patient is the best judge of the intensity of the pain. Conservative physician prescribing patterns and conservative administration patterns of nurses were identified as perceived barriers to adequate pain management by 51 and 44 percent of respondents, respectively. Less than 30 percent of respondents frequently counseled cancer pain patients and were unable to identify patients who have cancer pain as a major medical illness. Hospital pharmacists recommended adjunctive therapy more often than did community pharmacists (p = 0.013). Interventions in pain management regimens were more often conducted by hospital pharmacists than by community pharmacists (p = 0.049). Differences in availability of narcotics was noted among practice sites for some more potent narcotics. Of the pharmacists surveyed, only 43 percent had attended a continuing education program on cancer pain management. Ninety-six percent of respondents were interested in attending a continuing education program in the future., Conclusions: Pharmacists in North Carolina are aware that the undertreatment of cancer pain is a serious medical problem. Unfortunately, pharmacists appear to be unable to identify patients with cancer pain as a major medical problem; therefore, counseling activity is limited. Addiction is still perceived as a barrier by some pharmacists. Through organizations such as the North Carolina Pain Initiative, these problems can be addressed.

Objective: To evaluate the pharmacokinetics and pharmacodynamics of recombinant activated factor VII (rFVIIa)., Methods: Single-dose pharmacokinetics of three dose levels (17.5, 35, and 70 micrograms/kg) of rFVIIa were investigated in 15 patients with hemophilia with severe factor VIII or factor IX deficiency (with or without inhibitors) while they were in the nonbleeding state and during bleeding episodes. Factor VII clotting activity (FVII:C) was determined 5 minutes before and at 10, 20, and 50 minutes and 2, 4, 6, 8, 12, and 24 hours after rFVIIa administration. Model-independent pharmacokinetic analysis of FVII:C plasma concentration-time data included determination of plasma clearance, mean residence time, and volume of distribution. rFVIIa recovery was determined from the plasma FVII:C observed 10 minutes after administration. Pharmacodynamic assessments of prothrombin time, activated partial thromboplastic time, and Factor X values obtained concurrently with FVII:C samples were performed., Results: Sufficient data to allow pharmacokinetic parameter calculation were available for 25 nonbleeding episodes in 11 patients (17.5 micrograms/kg, n = 8; 35 micrograms/kg, n = 9; 70 micrograms/kg, n = 8) and for five bleeding episodes in three patients (17.5 micrograms/kg, n = 2; 35 micrograms/kg, n = 2; 35 micrograms/kg, n = 1). Recovery was calculated during 27 nonbleeding and 17 bleeding episodes. rFVIIa distribution volume is two to three times that of plasma. Median clearance was low--31.0 ml/hr.kg in nonbleeding episodes and 32.5 mg/hr.kg in bleeding episodes. In nonbleeding episodes, median mean residence time was 3.44 hours and median half-life was 2.89 hours. In bleeding episodes, the elimination rate appears to be higher, with a median mean residence time of 2.97 hours and a median half-life of 2.30 hours. Recovery was 45.6% during nonbleeding conditions and 43.5% during bleeding episodes (p = 0.0006); it was statistically lower with the highest dose level than with the 17.5 and 35 micrograms/kg doses (p = 0.007). A significant statistical relationship was observed between values of the prothrombin time and activated partial thromboplastin time, and values of FVII:C with use of maximum effect model., Conclusions: The pharmacokinetics of rFVIIa are linear in the dose range evaluated. The results suggest potential value of prothrombin time determination in the monitoring of rFVIIa therapy.

The purpose of this study is to describe patterns of pain, analgesic use, barriers to pain control, and various aspects of lifestyle affected by pain in hospice patients. Seventy-six charts of deceased patients were randomly selected of patients who had received care from Hospice of Wake County between August 1990 and August 1991. All patient's charts were reviewed from date of entry into hospice until death. Pain assessments were routinely performed at entry into hospice, then at one month intervals, and, thereafter, whenever a change in pain status occurred. The average number of pain assessments performed per patient was 2.7 (range 18). Pain intensity score increased as the number of pain assessments increased. Pain was described as occasional (25.2 percent), frequent (26.6 percent) or constant (24.1 percent). Most common analgesic medications were long-acting morphine sulphate (25.4 percent), acetaminophen and hydroxy/oxycodone combinations (20.1 percent) and NSAIDS (17.1 percent). Approximately 40 percent of all pain assessments reflected use of greater than one analgesic agent and prn and scheduled medications simultaneously. Eighty percent of all pain assessments prompted a recommendation to change the analgesic regimen and 62.5 percent of regimen changes were associated with improvement in pain status. Barriers to pain control and lifestyle alterations due to pain were identified. The positive findings in this report, compared to previous similar investigations, supports the use of the pain assessment document and guidelines for cancer pain management in use at the Hospice of Wake County.

Purpose/objectives: To provide an overview of the current attitudes and perceptions of oncology nurses regarding the relevance and measurability of quality of life (QOL) in patients with cancer., Design and Setting: Exploratory survey conducted at a scientific exhibit of QOL instruments at the 1990 Oncology Nursing Society Congress held in Washington, DC., Sample: Convenience sample of 621 nurses visiting the exhibit., Methods: Subjects completed two questionnaires addressing opinions regarding the impact of treatment on QOL, the importance of QOL as an outcome measure, the current status of QOL assessment, barriers to measuring QOL, and knowledge about QOL measurement tissues., Main Outcome Measures: Results of answers to questionnaire items overall as well as selected demographic variables., Findings: Chemotherapy was thought to have the greatest negative impact on QOL, and vomiting, nausea, and tiredness were judged to be the side effects of treatment that most commonly affected QOL. QOL was judged as important an outcome measure as tumor response, toxicity, and survival. Generally, nurses were knowledgeable regarding QOL measurement issues; however, many of the respondents indicated that they believed valid QOL instruments did not exist or that QOL could not be objectively quantified., Conclusions: Nurses value QOL as an outcome measure of cancer treatment but lack knowledge regarding its measurability, particularly with respect to reliable tools and available time to assess it well., Implications for Nursing Practice: Nurses can be instrumental in incorporating QOL measurement as an outcome of treatment and development of brief self-administered tools. Commentary on this research and author response is included at the conclusion of the article.

The safety and efficacy of recombinant DNA-produced factor VIIa (rFVIIa) was investigated in 15 haemophilic patients in non-bleeding states and during bleeding episodes (mild to moderate joint bleed). Patients with severe haemophilia A without inhibitors (n = 4), haemophilia A with inhibitors (n = 10), and haemophilia B with inhibitor (n = 1) received one or more doses of rFVIIa during 32 non-bleeding study episodes and 23 bleeding episodes. The study was an open, uncontrolled, dose-escalation (17.5 micrograms/kg, 35 micrograms/kg, 70 micrograms/kg) trial. Physical evaluation, laboratory assessment, and immunology testing were conducted at baseline, monthly for 3 months and every 3 months thereafter. The immediate safety of rFVIIa was assessed by monitoring of D-dimer, fibrinogen, platelet count, antithrombin III, thrombin-antithrombin complex, and alpha 2-antiplasmin 5 min before and at multiple times throughout the following 24 h. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) values were also obtained. Pain, swelling, joint circumference, and range of motion were recorded before administration of the initial dose of rFVIIa in bleeding patients and at 6, 12, and 24 h. Haemostatic response to rFVIIa was observed in patients with severe VIII and IX deficiency with and without inhibitors. Therapy with rFVIIa was judged effective in 19 of the 22 evaluable bleeding episodes at one or more time points. The 35 micrograms/kg and 70 micrograms/kg doses were associated with higher response rates at 6 and 12 h compared to the 17.5 micrograms/kg dose level. A second dose of rFVIIa was administered in 20 of the 22 bleeding episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

It is evident from the data presented above that nausea and vomiting are frequent side effects which are often persistent and distressing to patients. Evidence suggests, and intuitively it appears that avoidance of nausea and vomiting is important to the patients' ability to maintain their quality of life during the treatment period. It is of particular interest to note that in the literature reviewed in this paper standard antiemetic prescribing and practice were followed. It would, therefore, appear that available antiemetic agents are not always effective or may not be adequately employed. The toxicities associated with dopamine receptor antagonists, the current standard of antiemetic regimens, limit their usefulness in the clinical setting. In fact, the contribution of antiemetic therapy toxicities to the incidence of anxiety, fatigue, and restlessness which were commonly reported by patients in the studies reviewed should be considered. Additional effort to characterise the impact of nausea and vomiting on cancer patients' quality of life is needed. Clearly, the data available suggest that these symptoms should be included as part of the physical domain component of quality of life instruments used in cancer patients. Ideally, the instrument used should contain separate items for nausea and vomiting. Major side effects of antiemetic therapy should also be assessed since these may be as debilitating as the effects of nausea and vomiting. Increased awareness of total patient impact of emesis and antiemetic therapy will serve as an impetus for improvements in antiemetic therapy strategies and practices.

Nausea and vomiting following chemotherapy administration are common and often overlooked causes of impairment in cancer patients. The goal of this study was to explore the broad range of consequences associated with this specific acute toxicity of chemotherapy. Specific objectives were: (1) create and test scales specifically designed to assess the impact of chemotherapy-induced nausea and vomiting or patients' daily function; (2) examine changes in quality of life of cancer patients 3 days following chemotherapy administration; (3) assess the impact of chemotherapy-induced emesis on quality of life and patients' daily function; (4) identify medical and non-medical cost-related consequences associated with chemotherapy-induced emesis. Patients receiving intermittent bolus chemotherapy regimens on an outpatient basis were eligible for this survey. Four instruments were used: a patient maintained diary, the Functional Living Index-Cancer (FLIC), a newly created Functional Living Index-Emesis (FLIE) and an Item Check list for cost-related consequences. On Day 1, before chemotherapy, patients completed the FLIC and FLIE. Patients recorded episodes on vomiting, severity of nausea, anxiety, sedation, antiemetics self-administered, and adverse effects in diaries for 3 days following chemotherapy. The FLIC and FLIE were completed at the end of Day 3. The Item Check list of cost-related consequences was administered as a telephone survey on Day 5. Approximately 56% of 122 patients reported chemotherapy-induced emesis (CIE). A change in mean FLIC score indicating a decline in quality of life was observed for the CIE group (119 to 101) but not in the group who did not report emesis (124 to 122). Decline in FLIC and FLIE from before to after chemotherapy administration was greater for CIE patients (p = 0.001). FLIE scores indicated that CIE patients perceived that vomiting, and to a slightly lesser extent, nausea substantively influenced their ability to complete household tasks, enjoy meals, spend time with family and friends, and maintain daily function and recreation. Effect size calculations supported a significant negative relationship between occurrence of CIE and the direction and magnitude of functional living index change. An exploratory analysis (principal component followed by regression analysis) supported the hypothesis that side-effects produced by chemotherapy and antiemetic therapy significantly contributed to changes in quality of life observed.(ABSTRACT TRUNCATED AT 400 WORDS)

To determine the extent to which adverse drug reactions (ADRs) in elderly patients admitted to hospital are due to inappropriate prescribing, we examined 416 successive admissions of elderly patients to a teaching hospital. Interacting drug combinations and drugs with relative contra-indications (CIs) were common, but not as important in producing ADRs as drugs with absolute CIs or unnecessary drugs. Forty-eight patients (11.5% of admissions) were taking a total of 51 drugs with absolute CIs (3.8% of prescriptions). One hundred and seventy-five drugs were discontinued on or shortly after admission in 113 (27%) patients because they were deemed to be unnecessary. One hundred and three patients (27.0% of those on medication) experienced 151 ADRs of which 75 (49.7%) were due to drugs with absolute CIs and/or that were unnecessary, a significantly higher rate of ADRs (p less than 0.001) than observed for all prescriptions. Of 26 (6.3%) admissions attributed to ADRs, 13 (50%) were due to inappropriate prescriptions. The admission rate per prescription was significantly higher (p less than 0.001) for inappropriate than for appropriate drugs. We conclude that much drug-related morbidity in the elderly population may be avoidable, as it is due to inappropriate prescribing.

Cisplatin-based chemotherapy is the treatment of choice for metastatic testicular cancer; however, the safety of conventional regimens in renal transplant recipients has been questioned. The authors report the course of a renal transplant recipient successfully treated with a cisplatin-based chemotherapy regimen for testicular seminoma and review three additional cases that have been reported in the English language literature to date. Emphasis is placed on review of the safety, optimal administration, and appropriate monitoring of cisplatin and controversy regarding the need for continued administration of immunosuppressive therapy.

Pentostatin (2'-deoxycoformycin) is a unique antineoplastic agent that has proven valuable in the treatment of a number of lymphoid malignancies. Dose-limiting toxicities observed in clinical trials include central nervous system (CNS) effects and acute renal failure. Information regarding the incidence, duration, and severity of nausea and vomiting from published reports is conflicting and insufficient to provide recommendations for optimal supportive measures. We report the results of a phase I study where pentostatin was associated with a 20% incidence of vomiting following courses one and two (pentostatin alone). The third course of pentostatin administered concurrently with alpha interferon resulted in a 29% incidence of vomiting and by course four had increased to 50%. Grade of severity was similarly increased, and nausea and vomiting was the dose-limiting toxicity in 6 of 15 patients. Forty-two percent of all episodes of vomiting were delayed in onset (onset 24 hr after drug administration) and in over 80% of cases persisted for greater than 48 hr in duration. Potential mechanisms that may account for these findings, as well as recommendations regarding antiemetic therapy are provided.

Cisplatin-containing chemotherapy regimens are known to produce intense nausea and vomiting. Angiotensin II (AII) and vasopressin (AVP) have been shown to have emetic properties. The role of these two peptides on cisplatin-induced vomiting was investigated in beagle dogs. Cisplatin (2 mg/kg, IV over 5 min) produced consistent emesis in all dogs after a mean latency time of 144 +/- 4 min. Serum Angiotensin Converting Enzyme (ACE) and plasma AII levels did not significantly change 3 hr after cisplatin administration (at the time of nausea and emesis) in control animals. AVP levels rose from 0.3 pg/ml to 7.5 pg/ml 3 hrs after cisplatin. Complete inhibition of ACE with enalapril (given at 3 mg/kg p.o., 3 hrs prior to cisplatin) reduced AII levels by 70%, but failed to significantly modify the increase in AVP levels (7.2 +/- 2.2 pg/ml), the latency time to emesis (149 +/- 2 min) and the number of emetic episodes induced by cisplatin. These results suggest that AII does not mediate cisplatin-induced emesis, nor does it mediate the increase in AVP observed at the time of emesis. We propose that AVP may be a good marker for nausea and emesis, and that increases in AVP may be neurally-mediated. The large increase in circulating AVP may represent a desirable water conservation response in anticipation of fluid losses induced by vomiting.

Annual vaccination programs against influenza are aimed at decreasing the morbidity and mortality associated with an infection. Recent epidemics have resulted in 40,000 excess deaths reported. The success of an immunization program depends both on the composition of the annual vaccine and the targeting efficacy of the program. National estimates of targeting efficacy are reported at 20%. An evaluation performed in the author's ambulatory care practice in the spring of 1984 yielded an overall efficacy of 24% in targeting activities. Efforts to improve the targeting practices included enhanced practitioner and patient education about the vaccine, flagging of medication records for patients at risk, and adoption of CDC guidelines for categorizing patients based on the degree of risk. A subsequent evaluation in 1986 showed a significant improvement in targeting efficacy (40%; P less than .001). Subgroup analysis indicated that the targeting efficacy of the program was greatest for the high-risk patients (P less than .025). An overall immunization rate of at least 80% of patients at risk is our desired goal.

A young adult male patient presented with an excessively prolonged prothrombin time (greater than 90 sec) following approximately two weeks of therapy with oral warfarin sodium, in doses between 2.5 and 5 mg/d. Repeated administration of vitamin K and fresh frozen plasma was required to reverse the anticoagulation and maintain a normalized prothrombin time. Serial warfarin plasma concentration measurements were used to interpret the apparently unusual prothrombin time response profile and to detect the possibility of covert drug ingestion.

Thrombotic microangiopathy (TMA) is a serious toxicity associated with a small number of antineoplastic agents. A case report of a patient with probable cisplatin and bleomycin-induced TMA is presented. The basic triad of symptoms that occurs in the TMA syndrome include microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Cardiovascular, pulmonary, and neurologic complications also occur frequently. The pathogenesis of chemotherapy-associated thrombotic microangiopathy (C-TMA) has not been established. Proposed mechanisms include von Willebrand Factor abnormalities, decreased prostacyclin production, and immune complex formation. Treatment modalities have been unsuccessful and the majority of patients reported have died. Immunoperfusion with staphylococcal protein A is the most effective treatment available and this new technique appears promising. This article reviews the results of all cases of C-TMA reported to date in the English literature and discusses the theories of pathogenesis, clinical features, treatment, and treatment-related complications of the syndrome.

Nausea and vomiting are commonly recognized side effects of chemotherapy. However, the incidence and duration of these effects have not been systematically studied in a large outpatient oncology population. This survey was conducted over two consecutive 6-week periods in the adult oncology clinics of two university teaching hospitals. The objectives were: (1) to document the incidence and duration of chemotherapy-induced nausea and vomiting; (2) to identify variables that influence nausea and vomiting; and (3) to describe patterns of antiemetic prescribing and compliance. One hundred thirty-eight completed patient-maintained diaries were returned (70% response rate). Anticipatory nausea and vomiting were reported by 9.4% and 6.5% of patients, respectively. Fifty percent and 27% of patients reported nausea and vomiting, respectively, on the day chemotherapy was administered (day 1: acute nausea and vomiting phase). Percentages fell to 22% and 11% by day three and 14% and 2.5% on day 5. Of patients who reported nausea and vomiting during the five-day period, 52% and 33% experienced nausea and vomiting, respectively, during the delayed period only (days 2 through 5: delayed emesis phase). Emetogenicity of chemotherapy significantly influenced incidence and duration of those symptoms. Sixty-seven percent of patients reported taking antiemetics on one or more days during the survey period. Of patients who reported antiemetic use, 92% reported antiemetics on day 1, 51% on day 3, and 31% on day 5. At-home antiemetic use was related to the emetogenicity of chemotherapy received. Patients who receive moderate to strong emetogens as defined in this report should receive antiemetic therapy for a minimum of three days. Increasing the dose of antiemetic prescribed both in the clinic and at home may be of benefit.